Diffusion tensor imaging in familial Alzheimer's disease: Longitudinal and cross-sectional studies of early change

Diagnosis of Alzheimer‘s disease, the most common form of dementia, is difficult in its earlier stages. A number of different brain scanning techniques have recently been developed which may pick up very early changes in these individuals. One of these techniques is called diffusion imaging. This examines the microscopic structure of brain tissue, non-invasively. It also allows assessment of connections between parts of the brain - so called white matter tracts. Diffusion imaging therefore allows not just the assessment of how particular areas of brain may be degenerating, but also how the connections between areas are being affected.

Familial Alzheimer‘s disease is a rare form of Alzheimer‘s where the disease is inherited at a young age. Individuals from families with known genetic mutations have generously agreed to take part in prospective longitudinal studies. We propose to study individuals who are well, but who are at known risk of developing Alzheimer‘s disease. This will allow us to acquire high resolution brain scans, including this new technique of diffusion imaging in conjunction with detailed clinical and psychological assessments. We will examine whether this technique detects early changes and how this matches with the onset and progression of clinical cognitive problems.

As increasing numbers of therapies promising disease modification in Alzheimer‘s disease (AD) undergo development, the need for reliable biomarkers has never been more relevant. Targeting therapies to the early stages of the disease where they are most likely to be effective, and monitoring their effect on the pathological process, demands sensitive markers of early manifestation and progression of disease. Although rare, familial Alzheimer‘s disease (FAD) provides the unique opportunity to carry out prospective longitudinal study of individuals who are cognitively normal but are destined to develop the disease.

Diffusion imaging allows assessment of alterations in tissue microstructure which may be an early marker of pathological change. Diffusion tensor imaging (DTI) extends the modality to examine the integrity of white matter pathways and allows the assessment of connections between degenerating regions. It is now well established that grey matter losses and neuropsychological deficits are detectable many years prior to symptom onset in FAD mutation carriers. Degeneration of white matter tracts connecting these cortical areas and the concomitant effects of loss of connectivity have been less well studied, however there is evidence that these changes occur early.

The aim of this study is to investigate markers of early change using DTI in presymptomatic individuals at risk of FAD and in individuals mildly affected by familial and sporadic AD. We will use serial volumetric MRI and diffusion imaging, together with clinical and neuropsychological assessments, to study presymptomatic FAD mutation carriers, mildly affected individuals with FAD and young-onset sporadic AD, and age-matched controls. We will combine volumetric imaging and DTI to assess the relative contributions to, and relationship between, grey and white matter damage. In the FAD cohort, we will also have the opportunity to compare these results with changes detectable on amyloid imaging through PET scanning using the C11-PIB ligand.

In addition, we will, for the first time, look at longitudinal changes in diffusion and correlate these with changes in clinical and cognitive measures over time. Measurement of within-individual changes on imaging avoids some of the natural between-individual variability and may be a more sensitive and relevant marker of pathological change than a single assessment.

This study will derive new imaging biomarkers for the detection of early change in AD, and provide more general insights into the pathobiology of neurodegenerative disease.